The present invention relates to novel 1,4-piperidine and piperazine derivatives, to processes for preparing the novel derivatives, to novel intermediates useful in the process, to pharmaceutical compositions comprising the derivatives, and to the use of derivatives in the treatment of disorders of the central nervous system.
It has been disclosed in the scientific literature that certain disorders of the central nervous system may be treated using a modulator of sigma receptor function. Amongst compounds known to possess affinity for sigma ligands are certain piperidine and piperazine derivatives.
WO 91/09594 discloses compounds having affinity for sigma receptors, certain of which are piperidine or piperazine derivatives, and discloses that they are useful in the treatment of schizophrenia and other psychoses.
U.S. Pat. No. 5,736,546 discloses certain 1,4-(diphenylalkyl)piperazines having one phenyl group unsubstituted and the other phenyl group substituted by two alkoxy groups. One of the compounds disclosed is 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine. It is also referred to in the scientific literature as SA 4503. The compounds of U.S. Pat. No. 5,736,546 are said to be useful in the treatment of dementia, depression, schizophrenia, anxiety neurosis, diseases accompanying abnormal immune response, cryptorrhea and digestive ulcer.
WO 2004/110387 discloses that sigma ligands, in particular SA 4503, are also useful in the treatment of patients to facilitate neuronal regeneration after onset of a neurodegenerative disease, such as ischemic stroke, traumatic brain injury or spinal chord injury.
U.S. Pat. No. 5,389,630 discloses certain diamine compounds having cerebral protective action. The compound of Example 50 is a piperazine derivative, but the vast majority of the exemplified compounds are homopiperazine derivatives. The mechanism of action of the compounds is not discussed.
It has now been found that certain novel 1,4-piperidine and piperazine derivatives have high affinity for sigma receptors, in particular sigma-1 receptors.
According to one aspect, the present invention provides a compound of general formula (I)
in which:—
R1 represents a phenyl group that is unsubstituted or substituted by one, two or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group, a cyano group, and a halo(1-4C)alkoxy group;
m is 2, 3, 4 or 5;
X is CH or N;
n is 0, 1, 2, 3, 4 or 5, provided that when X is N, n is 2, 3, 4 or 5;
Y is O, NR2 or S;
R2 is hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl, or is as defined for R3; and
R3 represents indan-1-yl, indan-2-yl, 1,2,3,4-tetrahydronaphth-1-yl or 1,2,3,4-tetrahydronaphth-2-yl, each of which may bear a hydroxyl substituent on a non-aromatic carbon atom; (3-6C) cycloalkyl; or a phenyl group that is unsubstituted or substituted by one, two or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a cyano group; a phenyl group, an imidazolyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group and a halo(1-4C)alkoxy group;
or a pharmaceutically acceptable salt thereof.
Compounds according to the invention have been found to have high affinity for sigma receptors, in particular sigma-1 receptors.
As used herein, unless otherwise indicated, the term halogen atom includes fluorine, chlorine and bromine.
The term (1-2C)alkylenedioxy includes methylenedioxy and ethylenedioxy.
An example of a (1-4C) alkyl group is methyl. Other examples are ethyl, propyl, 2-propyl, butyl, 2-butyl and t-butyl.
The term halo(1-4C)alkyl as used herein includes perfluoro(1-4C)alkyl, such as trifluoromethyl.
An example of a (1-4C)alkoxy group is methoxy. Other examples are ethoxy, propoxy and 2-propoxy.
The term halo(1-4C)alkoxy as used herein includes perfluoro(1-4C)alkoxy, such as trifluoromethoxy.
Examples of a (3-6C) cycloalkyl group are cyclopentyl and cyclohexyl.
Referring to formula (I), examples of particular values for R1 are phenyl, benzo[1,3]dioxol-5-yl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-chlorophenyl, 3-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-fluoro-3,4-dimethoxyphenyl, 3-chloro-4-methoxyphenyl, 4-chloro-3-methoxyphenyl, 2-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl and 3-trifluoromethoxyphenyl.
Particular examples of values for R1 are phenyl, benzo[1,3]dioxol-5-yl, 2-fluorophenyl, 3,4-difluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxypheny, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl and 2-trifluoromethoxyphenyl.
Particular mention is made of compounds of formula (I) in which R1 represents 3,4-dimethoxyphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl, or 3,4,5-trimethoxyphenyl.
Examples of values for m are 2 and 3. An example of a particular value for m is 2.
Examples of particular values for n are 2 and 3. An example of a particular value for n is 2.
An example of a particular value for R2 is hydrogen.
Examples of particular values for Y are O and NH.
Examples of particular values for R3 are phenyl, benzo[1,3]dioxol-5-yl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-trifluoromethoxyphenyl, 2-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methylphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-biphenyl, 4-(1-imidazolyl)phenyl, 2-fluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-chloro-4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3,4,5-trimethoxyphenyl, and 4-trifluoromethoxyphenyl.
Particular examples for R3 are phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-isopropylphenyl, 4-cyanophenyl, 3,4,5-trimethoxy group, and 2-trifluoromethylphenyl.
Particular mention is made of compounds of formula (I) in which R3 represents a 4-fluorophenyl group.
It will be appreciated that certain compounds of formula (I) contain a centre of asymmetry. These compounds may therefore exist and be isolated in the form of stereoisomers. The present invention provides a compound of formula (I) in any stereoisomeric form.
It will also be appreciated that the compounds of formula (I) or their pharmaceutically acceptable salts may be isolated in the form of a solvate, and accordingly that any such solvate is included within the scope of the present invention.
Certain compounds of formula (I) have also been found to possess good selectivity for sigma-1 receptors as compared with sigma-2 receptors. This selectivity for sigma-1 receptors is particularly desirable, because selectivity for sigma-2 receptors can have undesired results. For example, sigma-2 receptors have been shown to play an important role in the sigma receptor-mediated neck dystonia in rats (Matsumoto R R, et al., Pharmacol. Biochem. Behav. 36, 151-155, 1996). For example microinjection of DTG (1,3-di-2-tolyl-guanidine, a sigma-1 and sigma-2 receptor agonist) induced neck dystonia in rats while injection of SA-4503 (a selective sigma-1 agonist) had no effect (Nakazawa M et al., Pharmacol biochem. Behav., 62, 123-126, 1999). In addition sigma-2 receptors have been implicated in the regulation of cell proliferation. Cytotoxic effects have been correlated with sigma-2 receptor ligands (Vilner and Bowen, Eur. J. Pharmacol Mol Pharmacol Sect 244, 199-201, 1993). Sigma-2 selective drugs can inhibit tumor cell proliferation through mechanisms that may involve apoptosis and intracellular calcium release (Aydar E et al., Cancer Research 64, 5029-5035, 2004). Compounds of formula (I) possessing good selectivity for sigma-1 receptors are therefore particularly preferred.
According to another aspect, therefore, the present invention provides a compound which is selected from    1-(3,4-Dimethoxyphenethyl)-4-(2-(4-fluorophenoxy)ethyl)piperidine;    1-(4-(Trifluoromethyl)phenethyl)-4-(2-phenoxyethyl)piperidine;    4-(2-(2-Fluorophenoxy)ethyl)-1-(3,4-dimethoxyphenethyl)piperidine;    1-(3,4-Dimethoxyphenethyl)-4-(2-phenoxyethyl)piperazine;    1-(3-Methoxyphenethyl)-4-(2-phenoxyethyl)piperazine;    1-(4-Methoxyphenethyl)-4-(2-phenoxyethyl)piperazine;    1-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(2-phenoxyethyl)piperazine;    1-(3,4-Difluorophenethyl)-4-(2-phenoxyethyl)piperazine;    1-Phenethyl-4-(2-phenoxyethyl)piperazine;    1-(3,4-Dimethoxyphenethyl)-4-(2-(4-chlorophenoxy)ethyl)piperazine;    4-(2-(4-(3,4-Dimethoxyphenethyl)piperazin-1-yl)ethyloxy)benzonitrile;and pharmaceutically acceptable salts thereof.
The above compounds have been found to possess good selectivity for sigma-1 over sigma-2 receptors.
The compounds of general formula (I) can be prepared by conventional processes.
According to another aspect, therefore, the present invention provides a process for preparing a compound of general formula (I), or a pharmaceutically acceptable salt thereof, which comprises
a) reducing a compound of general formula (II)
with a reducing agent;
b) for a compound of formula (I) in which X is N, reacting a compound of general formula (III)
in which each of Z1 and Z2 independently represents a leaving atom or group, with a compound of general formula (IV)R1—(CH2)m—NH2  (IV)or a corresponding compound in which one or two substituents on R1 are protected; or
c) for a compound of formula (I) in which X is N, reacting a compound of general formula (V)
with a compound of general formula (VI)Z3—(CH2)n—Y—R3  (VI)in which Z3 represents a leaving atom or group;
followed by removing any protecting group and, optionally, forming a pharmaceutically acceptable salt.
Referring to process step a), the reducing agent can conveniently be a borane (BH3), a borohydride reducing agent, such as sodium borohydride, or an alkali metal aluminium hydride, such as lithium aluminium hydride. The reduction is conveniently performed in the presence of a solvent such as an ether, for example tetrahydrofuran. The temperature at which the reduction is carried out is conveniently in the range of from −25 to 100° C., such as from −10 to 40° C.
Compounds of general formula (II) can be prepared by reacting a compound of general formula (VII)
in which Z4 represents a leaving atom or group, such as a p-toluenesulfonyloxy group, with a compound of general formula (VIII)H—Y—R3  (VIII).
Compounds of general formula (VII) can be prepared from a corresponding compound of general formula (IX),
for example by reaction with a sulfonyl halide, such as p-toluenesulfonyl chloride.
Compounds of general formula (IX) can be prepared by reacting a compound of general formula (X)
with a compound of general formula (XI)R1—(CH2)m-1COOH  (XI)or a reactive derivative thereof, using standard amide bond coupling conditions.
Alternatively, compounds of general formula (II) can be prepared by reacting a compound of general formula (XII)
with a compound of general formula (XI), or a reactive derivative thereof, using standard amide bond coupling conditions.
Compounds of general formula (XII) can be prepared by deprotecting a compound of general formula (XIII)
in which P1 represents an amino protecting group, such as t-butoxycarbonyl.
Compounds of general formula (XIII) can be prepared from the corresponding compounds of general formula (XIV)
following the procedure for preparing a compound of general formula (II) from a compound of general formula (IX).
Referring to process step b), the leaving atoms or groups represented by Z′ and Z2 may be, for example, hydrocarbylsulfonyloxy groups, such as methanesulfonyloxy or p-toluenesulfonyloxy, or halogen atoms, such as chlorine atoms.
The reaction is conveniently performed at a temperature in the range of from 0 to 100° C., such as from 50 to 90° C. Convenient solvents include organic solvents, for example amides such as dimethylformamide. The reaction is conveniently performed in the presence of a base, for example an alkali metal carbonate such as potassium carbonate. The reaction may be performed in the presence of a catalyst, such as sodium iodide.
Compounds of general formula (III) can be prepared from the corresponding compounds of general formula (XV)
for example by reaction with thionyl chloride to afford a compound of formula (III) in which Z1 and Z2 represent chlorine atoms.
Compounds of general formula (XV) can be prepared by reacting a compound of general formula (XVI)
with a compound of general formula (XVII)Z5—(CH2)n—Y—R3  (XVII)in which Z5 represents a leaving atom or group, for example a halogen atom such as a bromine atom.
Referring to process step c), the leaving atom or group represented by Z3 may be, for example, a hydrocarbylsulfonyloxy group, such as p-toluenesulfonyloxy. Convenient solvents include ketones, such as acetone. The reaction is conveniently performed at a temperature in the range of from 0 to 100° C.
A pharmaceutically acceptable salt may be formed by a conventional method, such as by reacting a compound of formula (I) with a pharmaceutically acceptable acid, such as hydrochloric acid.
Certain of the intermediates, for example compounds of formula (II), may be novel. The invention also provides the entire novel intermediates disclosed herein.
The compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature or transdermally. The compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.
According to another aspect, the present invention provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinabove, together with a pharmaceutically acceptable diluent or carrier.
According to another aspect, the present invention provides the compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
According to another aspect, the present invention provides the use of the compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder responsive to a modulator of sigma receptor function.
According to another aspect, the present invention provides a method of treating a condition responsive to a modulator of sigma receptor function in a patient requiring treatment, which comprises administering to said patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The subject may be a human or a non-human animal, such as a non-human mammal, for example a cat, dog, horse, cow or sheep.
The disorder responsive to a sigma receptor modulator may be, for example, a disorder of the central nervous system, such as a neurological disorder or a psychiatric disorder that has been linked to sigma receptors. Examples of neurological disorders include cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia (e.g. associated with stroke or cardiac arrest); spinal cord trauma; head trauma; multiple sclerosis, Alzheimer's Disease; Huntington's Chorea; amyotrophic lateral sclerosis; AIDS-induced dementia; muscular spasms; convulsions; drug tolerance, withdrawal, and cessation (i.e. opiates, benzodiazepines, nicotine, cocaine, or ethanol); ocular damage and retinopathy; cognitive disorders; idiopathic and drug-induced Parkinson's Disease; pain; and movement disorders such as tardive dyskinesia. Examples of psychiatric disorders that are treated with a compound of formula I include schizophrenia, anxiety and related disorders (e.g. panic attack and stress-related disorders), depression, bipolar disorders, psychosis, and obsessive compulsive disorders.
The compounds according to the invention are of particular interest for use as neuroprotective agents and in the treatment of patients to facilitate neuronal regeneration and functional recovery after onset of a neurodegenerative disease, in particular ischemic stroke, traumatic brain injury, spinal cord injury, and multiple sclerosis.
The dosage of the compounds of formula (I) will depend upon the nature and severity of the condition being treated, the administration route and the size and species of the subject. In general, quantities in the range of from 0.01 to 100 mg/kg bodyweight will be administered.
As used herein, the term “treatment” includes prophylactic use. The term “effective amount” refers to the amount of the compound of formula (I) that is effective to reduce or inhibit the development of the symptoms of the disorder being treated.
The compound according to the invention may be administered alone or in combination with another therapeutic agent having a different mode of action.
The ability of a compound to bind to a sigma receptor may be demonstrated by one or more of the following tests.
Sigma-1 (σ1) and sigma-2 (σ2) receptor binding assays are carried out in membranes from HEK-293 (Human Embryonic Kidney) cells.
Membrane Preparation:
Confluent HEK-293 cells are harvested in PBS/5 mM EDTA. They are centrifuged at 2000 rpm for 5 min and then washed two times in PBS. Cells are homogenized in 20 mM Tris-HCL (pH=7.5) containing 5 mM EDTA, 0.5 mM PMSF and 0.5 μg/ml leupeptin using a Dounce homogenizer and sonicated for 5 minutes.
Nuclear debris and intact cells are removed by centrifugation at 3000 rpm for 10 minutes at 4° C. The supernatant is centrifuged at 12000 rpm for 30 minutes and the resulting pellet is resuspended in 25 mM Tris-HCL (pH=7.5), 25 mM Mg2Cl, 10% sucrose containing 0.5 mM PMSF, 2 mM AEBSF, 1 mM EDTA, 130 μM bestatin, 14 μM E-64, 1 μM leupeptin and 0.3 mM aprotinin.
Proteins are determined using the Bio Rad Protein Assay Dye Reagent and the membranes are aliquoted and frozen at −80° C.
σ1 Receptor Binding Assay
The binding assays are performed in 96-well plates.
σ1 receptors are labeled using the al selective probe (+)-[3H] Pentazocine (Bowen W D et al, Mol Neuropharmacol 3, 117-126, 1993).
Total binding is determined by incubating 50 μg of HEK-293 cell membranes with 10 nM (+)-[3H]-pentazocine (Perkin-Elmer, 35 Ci/mmol) and assay buffer (50 mM Tris-HCl, pH=8.3) in a total volume of 200 μl. Non specific binding is determined in the presence of 10 μM unlabeled pentazocine. For competition experiments, 50 μl of displacing compound is added at 8 different concentrations. Incubations are carried out for 120 min at 37° C. Assays are terminated by dilution with ice-cold 10 mM Tris-HCl, pH=8.3 and vacuum filtration through glass fibers using a Skatron cell harvester from Molecular Devices. The filters are washed three times and the membrane-bound radioactivity is determined in a Microbeta scintillation counter.
Filters are soaked in 0.5% polyethyleneimine for 1 hour before use.
Specific binding is determined by subtraction of non specific binding from total binding. IC50 values (concentration of competing ligand required for 50% inhibition of [3H]-pentazocine binding) are analyzed by non-linear regression fit using the GraphPad Prism software.
σ2 Receptor Binding Assay
The binding assays are performed in 96-well plates
σ2 receptors are labeled using [3H] DTG (Di-o-tolylguanidine), under conditions in which σ1 receptors are masked with the al selective compound pentazocine (Hellewell S B et al, Eur. J. Pharmacol, 268, 9-18, 1994).
Total binding is determined by incubating 50 μg of HEK-293 cell membranes with 10 nM [3H]-DTG (Perkin-Elmer, 58 Ci/mmol) in the presence of 10 μM pentazocine and assay buffer (50 mM Tris-HCl, pH=8.3) in a total volume of 200 μl. Non specific binding is determined in the presence of 10 μM unlabeled DTG. For competition experiments, 50 μl of displacing compound is added at 8 different concentrations. Incubations are carried out for 120 min at 37° C. Assays are terminated by dilution with ice-cold 10 mM Tris-HCl, pH=8.3 and vacuum filtration through glass fibers using a Skatron cell harvester from Molecular Devices. The filters are washed three times and the membrane-bound radioactivity is determined in a Microbeta scintillation counter.
Filters are soaked in 0.5% polyethyleneimine for 1 hour before use.
Specific binding is determined by subtraction of non specific binding from total binding. IC50 values (concentration of competing ligand required for 50% inhibition of [3H]-DTG binding) are analyzed by non-linear regression fit using the GraphPad Prism software
The compounds exemplified herein have all been found to have an IC50 of less than 700 nM in the σ1 receptor binding assay.
The following examples illustrate the invention.